An essential event in the development of the neural retina is the transition of proliferating progenitors to postmitotic differentiated retinal neurons. Inhibition of this process alters the complement of cell types required for normal retinal organization and function. Proneural basic helix-loop-helix (bHLH) transcription factors play a central role in regulating the commitment of retinal progenitor cells to a differentiated retinal neuron fate. The Ath5 gene is required for the genesis of retinal ganglion cells (RGCs). The long-term goal of this proposal is to define the molecular pathway by which Ath5 regulates retinal neurogenesis. Ath5 expression is tightly coupled with the onset of retinal neurogenesis, and the timing of its expression is important for its ability to regulate RGC differentiation. The first aim of the proposal will focus on characterizing the transcriptional regulatory mechanisms that provide spatial and temporal control of Ath5 expression. Next, to understand how Ath5 drives retinal differentiation it is important to investigate the function of genes that are regulated by Ath5 during retinal development. One of these Ath5 target genes, SBT1 (shared bHLH target 1), is a novel gene that functions as an essential effector for proneural bHLH factors in the developing retina. To understand the function of this novel gene, Aim 2 will focus on testing a predicted interaction between SBT1 and histone deactylase, while Aim 3 will be directed towards defining the molecular pathways that are dependent upon SBT1 during eye development. This work will advance our understanding of the mechanisms controlling retinal neuron differentiation, and will reveal the function of an important new gene in the proneural regulatory pathway, which could provide insight into developmental disorders affecting the retina. Ultimately, a detailed understanding of the factors determining retinal neuron fate in vivo will impact future efforts at replacing neurons lost to disease. PUBLIC HEALTH RELEVANCE: An important goal of our research is to understand how cells in the retinal are generated during early eye development, since we may gain a better understanding of how these processes are disrupted in pathological situations, such as congenital disorders affecting vision. A long-term hope is that we may ultimately be able to manipulate the differentiation of retinal stem cells or progenitors to treat retinal degenerative diseases. Our work will contribute to this effort by characterizing the mechanisms underlying retinal neuron development.